WO2018164043A1 - Composé précurseur marqué au fluor radioactif, et procédé de production d'un composé marqué au fluor radioactif utilisant ce dernier - Google Patents

Composé précurseur marqué au fluor radioactif, et procédé de production d'un composé marqué au fluor radioactif utilisant ce dernier Download PDF

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WO2018164043A1
WO2018164043A1 PCT/JP2018/008287 JP2018008287W WO2018164043A1 WO 2018164043 A1 WO2018164043 A1 WO 2018164043A1 JP 2018008287 W JP2018008287 W JP 2018008287W WO 2018164043 A1 WO2018164043 A1 WO 2018164043A1
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labeled
precursor compound
group
compound
general formula
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PCT/JP2018/008287
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English (en)
Japanese (ja)
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真登 桐生
浩章 市川
侑紀 奥村
浩士 田中
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日本メジフィジックス株式会社
国立大学法人東京工業大学
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Application filed by 日本メジフィジックス株式会社, 国立大学法人東京工業大学 filed Critical 日本メジフィジックス株式会社
Priority to AU2018232211A priority Critical patent/AU2018232211A1/en
Priority to CN201880012981.8A priority patent/CN110312704A/zh
Priority to CA3055417A priority patent/CA3055417A1/fr
Priority to ES18764052T priority patent/ES2909126T3/es
Priority to SG11201908066XA priority patent/SG11201908066XA/en
Priority to KR1020197029004A priority patent/KR20190126357A/ko
Priority to JP2019504564A priority patent/JP7165853B2/ja
Priority to EP18764052.9A priority patent/EP3594200B1/fr
Priority to US16/491,046 priority patent/US20200009273A1/en
Publication of WO2018164043A1 publication Critical patent/WO2018164043A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/76—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/77—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing carboxyl groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/17—Unsaturated ethers containing halogen
    • C07C43/174—Unsaturated ethers containing halogen containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the present invention relates to a novel radioactive fluorine-labeled precursor compound and a method for producing a radioactive fluorine-labeled compound using the precursor compound.
  • a compound in which a leaving group is bonded to a fluorine labeling site of a target substrate is prepared as a labeling precursor compound, and this labeling precursor compound is reacted with a radioactive fluoride ion F. It is often done by. And this reaction is generally performed using a small amount of radioactive fluoride ions F in a large amount of label precursor compound. Therefore, purification of the resulting radioactive fluorine-labeled compound is usually carried out by separating it from a large amount of unreacted labeled precursor compound by the HPLC method.
  • Patent Documents 1 and 2 prepare a compound in which the leaving group portion of the labeled precursor compound is modified with Compound M (purified portion) as a labeled precursor compound. It is proposed that the species containing the purified moiety M can be easily separated from other species that do not contain the purified moiety M by reacting with a nucleophile such as radioactive fluoride ion F.
  • Patent Document 3 The applicant has already filed a patent application for a labeling precursor compound and a labeling method using a new leaving group different from the conventional leaving group.
  • Patent Document 1 The method described in Patent Document 1 is based on the concept of chemically reacting an active group fixed to a resin with respect to a purified portion M of a precursor compound after a radiofluorination reaction. For this reason, it is necessary to prepare resins such as adversely affecting the radiofluorination rate, introducing special active groups, and adding additional reaction conditions such as heating and addition of reagents after the radiofluorination reaction. There was a problem such as.
  • Patent Document 2 The method described in Patent Document 2 is based on the concept of facilitating separation of radiolabeled compounds by setting the difference between logD of the labeled precursor compound and logD of the radiolabeled compound to 1.5 or more.
  • the types of leaving groups disclosed in Patent Document 2 are limited, and it is difficult to design according to the characteristics of each substrate, and synthetic problems such as the use of deleterious chlorosulfonic acid must be used. There was also. Moreover, further improvement has been demanded for the purity of the separated radiolabeled compound.
  • Patent Document 3 is limited to a compound having a neopentyl group as a substrate, and has not paid attention to application to a compound having no neopentyl group.
  • the present invention enables a flexible leaving group design, maintains the radiofluorination rate to the same level as the conventional method, and converts the radioactive fluorine-labeled compound into an unreacted precursor compound by a simple purification method after the radiofluorination reaction. It is an object to provide a method that can be separated and purified.
  • the present inventors have introduced a hydrophobic amide tag into the benzene ring of the leaving group consisting of a benzenesulfonyloxy group, thereby increasing the radiofluorination rate. While maintaining the same level as the conventional method, it was found that a method capable of separating and purifying the radioactive fluorine-labeled compound from the unreacted precursor compound by a simple purification method after the radiofluorination reaction was found, and the present invention was completed. .
  • a method for producing a radioactive fluorine-labeled compound is provided.
  • a labeling precursor compound for the radioactive fluorine labeling reaction a compound represented by the above general formula (2), that is, a hydrophobic amide substituent is added to the benzene ring of the benzenesulfonyloxy group which is a leaving group. Since it was decided to use the introduced compound, the radiofluorinated compound was separated from the unreacted precursor compound by a simple purification method after the radiofluorination reaction while maintaining the radiofluorination rate at the same level as the conventional method. can do.
  • Radiofluorine-labeled precursor compound of the present invention is a precursor compound of a radiofluorine-labeled compound represented by the above general formula (1) and has a structure represented by the above general formula (2). is there.
  • the clogP (clogP (1) ) of the radioactive fluorine-labeled compound represented by the general formula (1) is preferably ⁇ 1.4 to 5.0, more preferably 2.0 to 5.0.
  • the labeling precursor compound includes clogP (clogP (1) ) as a radioactive fluorine-labeled compound represented by the general formula (1) and clogP (clogP (2) ) as a precursor compound represented by the general formula (2).
  • the difference (clogP (2) -clogP (1) ) is preferably designed to be 2 or more, more preferably 3 or more, still more preferably 5 or more, and particularly preferably 8 or more.
  • the upper limit is not particularly limited, but the difference of clogP (clogP (2) -clogP (1) ) is preferably 50 or less, and 30 or less is more practical considering the solubility of the precursor compound in the reaction solution. is there. By doing so, after the radioactive fluorine labeling reaction, the unreacted precursor compound and the target radioactive fluorine-labeled compound can be separated easily and in a short time by simple column chromatography such as a reverse phase cartridge column.
  • examples of the alkyl group for R 1 and R 2 include linear or branched alkyl groups having 1 to 30 carbon atoms, preferably 4 to 24, more preferably 8 to 18 carbon atoms. And a linear alkyl group is preferred.
  • examples of the monocyclic aryl group for R 1 and R 2 include a phenyl group, and examples of the condensed polycyclic aryl group include a naphthyl group and an anthracenyl group.
  • a hydrogen atom may be substituted with an alkyl group, an alkoxy group, a halogen atom, or the like.
  • R 1 and R 2 may be the same or different, but are preferably the same group.
  • the group represented by —CONR 1 R 2 of the precursor compound of the present invention may be bonded to any of the meta position, ortho position and para position of the phenyl group, but is preferably bonded to the para position.
  • halogen means any one of fluorine, chlorine, bromine and iodine.
  • examples of the alkyl group for R 3 include linear or branched alkyl groups having 1 to 4 carbon atoms, and examples of the alkoxy group for R 3 include linear chains having 1 to 4 carbon atoms. Or a branched alkoxy group is mentioned.
  • p represents an integer of 0 to 4, but when p is 0, that is, the phenyl group of the compound of the general formula (2) is substituted with other than —CONR 1 R 2. If not, it is preferable.
  • the radioactive fluorine-labeled precursor compound of the present invention is preferably a compound of the general formula (2): —CONR 1 R 2 (R 1 and R 2 are each independently a linear alkyl group having 1 to 30 carbon atoms, or , A substituted or unsubstituted fused polycyclic aryl group is preferred) bonded to the para position and p is 0.
  • L represents a linear alkyl group (linker) that may contain an ether group having 1 to 6 carbon atoms.
  • L is, for example, a group represented by * —O (CH 2 ) n —, * — (CH 2 ) n — or * — (OCH 2 CH 2 ) m —, where n is an integer of 1 to 5, m is an integer of 1 to 3, and * represents a binding site with S. ].
  • the compound represented by the general formula (1) can be appropriately used as a radiopharmaceutical, and for example, a group represented by the following formula (S-1) Or a group represented by the following formula (S-2).
  • S ′ is a part of S, q is 0 or 1, and an asterisk is a binding site to L.
  • S ′ is a part of S, X 1 and X 3 each independently represent a hydrogen atom or a halogen atom, and X 2 represents a hydrogen atom, a halogen atom or Although it represents a nitrile group, at least one of X 1 , X 2 and X 3 is a halogen atom, and an asterisk is a bonding site with L.
  • specific examples of the group represented by the above formula (S-1) include, for example, the following formulas (S-3), (S-4), (S-5) and (S-6).
  • Groups. [Wherein q is the same as in the above formula (S-1), R 11 is a halogen atom, and an asterisk represents a binding site to L. ] [Wherein q is the same as in the above formula (S-1), J is O, S, NH or NMe, and an asterisk indicates a binding site to L. Here, Me represents a methyl group. ] [Wherein q is the same as in the above formula (S-1), Z is carbon or nitrogen, Me represents a methyl group, and an asterisk represents a binding site to L. ] [Wherein q is the same as in the above formula (S-1), Pg 1 represents an amino-protecting group, Pg 2 represents a carboxyl-protecting group, and an asterisk represents a binding site to L. Show. ]
  • q is preferably 1.
  • S is a group represented by the above formula (S-3)
  • L is a group represented by * —O (CH 2 ) n — [* is a bonding site with the above formula (S-3).
  • n is an integer of 1 to 5, and preferably an integer of 2 to 4.
  • q is preferably 0 and J is preferably O.
  • L is a group represented by * —O (CH 2 ) n — [* is a bonding site with the above formula (S-4).
  • n is an integer of 1 to 5, preferably 2.].
  • specific examples of the group represented by the formula (S-2) include a group represented by the following formula (S-7).
  • R 12 represents a hydrogen atom, a halogen atom, or CO 2 R a
  • R a represents the number of carbon atoms 1-10 alkyl groups are shown, and an asterisk shows a binding site with L.
  • R 12 is preferably a hydrogen atom
  • X 1 is preferably a hydrogen atom or a halogen atom
  • X 2 is preferably a halogen atom independently of X 1
  • X 3 is A hydrogen atom is preferred.
  • S is a group represented by the above formula (S-7)
  • L is a group represented by * — (CH 2 ) n — [* is a bonding site with the above formula (S-7).
  • N is an integer of 1 to 5, preferably 2 or 3.] is preferable.
  • substrate S examples include groups represented by the following formula (S-8). [Wherein, X 4 represents a halogen atom or a methyl group, R 13 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and an asterisk represents a bonding site with L. ]
  • X 4 is preferably a halogen atom, and R 13 is preferably a methyl group.
  • L is a group represented by * — (CH 2 ) n — [* is a bonding site with the above formula (S-7).
  • N is an integer from 1 to 5, and preferably n is 3.
  • radiolabeled compound of the general formula (1) obtained from the label precursor compound of the present invention examples include various radiopharmaceuticals, preferably those used as diagnostic agents by positron emission tomography (PET),
  • PET positron emission tomography
  • the above formula (S-3) is employed as the substrate S
  • amyloid affinity compounds disclosed in International Publication No. 2007/135890 can be mentioned.
  • myocardial perfusion imaging compounds for example, Flurpiridaz etc.
  • the radiofluorine-labeled precursor compound of the present invention includes, for example, a sulfonyl fluoride corresponding to a leaving group with respect to a compound (OH form) in which a hydroxyl group is bonded to a site where radiofluorine is introduced as shown in SCHEME 1 below.
  • DBU diazabicycloundecene
  • the step of reacting the radiofluorine-labeled precursor compound represented by the general formula (2) with [ 18 F] fluoride ion By subjecting to the (radiofluorine labeling reaction step), the radiofluorine labeled compound represented by the general formula (1) can be produced.
  • the radioactive fluorine labeling reaction is preferably performed in an inert solvent in the presence of a base.
  • [18 F] using the [18 O] was produced from water [18 F] fluoride ion solution by cyclotron as fluoride ions, as a base, for example, tetrabutylammonium, or potassium carbonate / crypto Using Fix 222, the reaction is carried out in a suitable solvent such as an aprotic solvent such as acetonitrile, N, N-dimethylformamide or dimethyl sulfoxide at a temperature of 20 to 120 ° C., and the above general formula (1) Can be obtained.
  • This radioactive fluorine labeling reaction can be carried out in a synthesizer equipped with a reaction vessel and a shield.
  • the synthesizer may be an automatic synthesizer that automates all the steps.
  • the compound of the above general formula (1) which is the target compound, can be purified according to a solid phase extraction method using a reverse phase cartridge column.
  • the unreacted precursor compound that is, the compound represented by the general formula (2)
  • the hydrophobicity is high. Therefore, a method utilizing this difference in hydrophobicity, for example, the reaction mixture obtained in the above-mentioned radiofluorine labeling reaction step is added to a reverse phase cartridge column packed with octadecyl silica gel or the like to add [ 18 F] fluoride ion.
  • an appropriate elution solvent is passed through the column to elute the compound of the general formula (1), which is the target compound, and separate and recover it.
  • the elution solvent include water-soluble solvents such as acetonitrile, ethanol, t-butanol, and methanol, or a mixed solution of these with water.
  • the compound of the above general formula (1), which is the recovered target compound can be subjected to deprotection or the like as necessary to obtain the target compound.
  • Step 1 Synthesis of 4- ( dibutylcarbamoyl) benzenesulfonate fluoride
  • Dibutylamine (280 ⁇ L, 1.60 mmol) was dissolved in dichloromethane (12 mL), triethylamine (0.25 mL, 1.8 mmol) was added, and the mixture was cooled to 0 ° C. After that, 4-fluorosulfonylbenzoic acid chloride (233 mg, 1.05 mmol) was added and stirred at 0 ° C. for 5 hours. After completion of the reaction, the reaction solution was added to 1 mol / L hydrochloric acid and extracted twice with ethyl acetate.
  • Step 2 Synthesis of 2-([1,1'-biphenyl] -4-ylmethoxy) ethanol Dissolve potassium t-butoxy (444 mg, 4.4 mmol) in ethylene glycol (4.4 mL, 78.9 mmol) A solution of (bromomethyl) -1,1′-biphenyl (1.8 g, 4.386 mmol) in tetrahydrofuran (20 mL) was added, and the mixture was stirred at 65 ° C. for 6.5 hours. t-Butoxy potassium (101 mg, 1.1 mmol) was added, and the mixture was stirred at 65 ° C. for 1.5 hours.
  • Step 3 Synthesis of Precursor Compound 1 2-([1,1′-biphenyl] -4-ylmethoxy) ethanol (52 mg, 0.22 mmol) was dissolved in acetonitrile (2.0 mL) and cooled to 0 ° C. Diazabicycloundecene (79 ⁇ L, 0.50 mmol) and 4- (dibutylcarbamoyl) benzenesulfonic acid fluoride (88 mg, 0.26 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added and extraction was performed twice with ethyl acetate.
  • Step 1 Synthesis of 4- ( dihexylcarbamoyl) benzenesulfonate fluoride
  • Dihexylamine (176 ⁇ L, 0.75 mol) was dissolved in dichloromethane (12 mL), triethylamine (0.13 mL, 1.25 mmol) was added and cooled to 0 ° C. Then, 4-fluorosulfonylbenzoic acid chloride (151 mg, 0.68 mmol) was added and stirred at 0 ° C. for 3 hours. After completion of the reaction, the reaction solution was added to 1 mol / L hydrochloric acid and extracted twice with ethyl acetate.
  • Step 2 Synthesis of Precursor Compound 2 2-([1,1′-biphenyl] -4-ylmethoxy) ethanol (50 mg, 0.22 mmol) was dissolved in acetonitrile (2.0 mL) and cooled to 0 ° C. Diazabicycloundecene (79 ⁇ L, 0.50 mmol) and 4- (dibutylcarbamoyl) benzenesulfonic acid fluoride (85 mg, 0.22 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added and extraction was performed twice with ethyl acetate.
  • Step 1 Synthesis of 4- (didodecylcarbamoyl) benzenesulfonic acid fluoride
  • Didodecylamine 500 mg, 2.70 mmol
  • dichloromethane 23 mL
  • triethylamine 0.63 mL, 4.50 mmol
  • 4-fluorosulfonylbenzoic acid chloride 500 mg, 2.25 mmol
  • 1 mol / L hydrochloric acid was added to the reaction solution, and extracted three times with ethyl acetate.
  • Step 2 Synthesis of 2-([1,1′-biphenyl] -4 -ylmethoxy) ethyl-4- (didodecylcarbamoyl) benzenesulfonate (precursor compound 3) 2-([1,1′-biphenyl] -4 -Ilmethoxy) ethanol (32 mg, 0.14 mmol) was dissolved in dichloromethane (1.4 mL) and cooled to 0 ° C. before diazabicycloundecene (50 ⁇ L, 0.33 mmol) and 4- (didodecylcarbamoyl) benzene.
  • Step 1 Synthesis of 4- (dioctadecylcarbamoyl) benzenesulfonate fluoride
  • Dioctadecylamine (282 mg, 0.54 mmol) was dissolved in dichloromethane (1 mL), triethylamine (0.13 mL, 0.90 mmol) was added, and 0 ° C.
  • 4-fluorosulfonylbenzoic acid chloride 100 mg, 0.45 mmol
  • water was added to the reaction solution, and extracted with chloroform three times. The combined chloroform layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 2 Synthesis of 2-([1,1′-biphenyl] -4 -ylmethoxy) ethyl-4- (dioctadecylcarbamoyl) benzenesulfonate (precursor compound 4) 2-([1,1′-biphenyl] -4 -Ilmethoxy) ethane-1-ol (30 mg, 0.13 mmol) was dissolved in dichloromethane (1.3 mL) and cooled to 0 ° C., then diazabicycloundecene (47 ⁇ L, 0.32 mmol) and 4- (di-) Octadecylcarbamoyl) benzenesulfonic acid fluoride (112 mg, 0.16 mmol) was added and stirred at room temperature for 18 hours.
  • Step 1 Synthesis of 2-([1,1′-biphenyl] -4 -ylmethoxy) ethyl-4-methylbenzenesulfonate 2-([1,1′-biphenyl] -4-ylmethoxy) ethanol (55 mg, 0.24 mmol) ) was dissolved in dichloromethane (2 mL), 1,4-diazabicyclo [2,2,2] octane (86 mg, 0.77 mmol) and p-toluenesulfonyl chloride (69 mg, 0.36 mmol) were added, and 4. was added at room temperature. Stir for 5 hours. After completion of the reaction, water was added and extraction was performed twice with ethyl acetate.
  • Step 4 Synthesis of Precursor Compound 6 2-([1,1′-Diphenyl] -4-ylmethoxy) -ethanol (50.6 mg, 0.222 mmol) was dissolved in dichloromethane (2.0 mL) and cooled to 0 ° C. Then, perform steps 1-3 according to the method described in Example 1 of 1,4-diazabicyclo [2.2.2] octane (37.4 mg, 0.333 mmol), and International Publication Pamphlet WO2011 / 006610.
  • Step 1 Synthesis of 4-([2-fluoroethoxy] methyl) -1,1′-biphenyl 2-fluoroethanol (86 mg, 0.77 mmol) was dissolved in tetrahydrofuran (1.4 mL) and cooled to 0 ° C. , Sodium hydride (3.2 mg, 0.14 mmol) was added and stirred for 10 minutes. Subsequently, 4- (bromomethyl) -1,1′-biphenyl (50 mg, 0.20 mmol) was added, followed by stirring at room temperature for 18 hours. After completion of the reaction, saturated aqueous ammonium chloride was added, and extraction was performed 3 times with chloroform.
  • Comparative Example 3 Radiofluorination Using Conventional Precursor Compounds: Preparation of 4-[(2- [ 18 F] fluoroethoxy) methyl] -1,1′-biphenyl Comparative Examples 1 and 2 as precursor compounds The same procedure as in Example 5 was performed except that the precursor compounds 5 and 6 synthesized by the method shown in FIG.
  • the precursor compounds 1 to 4 of the examples had less amount of the precursor mixed than the conventional precursor compounds 5 and 6. Moreover, about the precursor compounds 1, 3, and 4, the amount of non-radioactive impurities whose structure was unknown was also smaller than that of the conventional compound.
  • Step 6 Synthesis of Precursor Compound 7 2- [4 ′-(2-hydroxyethoxy) phenyl obtained by performing Steps 1 to 5 according to the method described in Example II-14 of International Publication Pamphlet WO2007 / 135890 ] -6-iodoimidazo [1,2-a] pyridine (100 mg, 0.263 mmol) was dissolved in acetonitrile (10.0 mL), cooled to 0 ° C., and then 1,8-diazabicyclo [5.4.0].
  • Example 7 Synthesis of Amyloid Beta Imaging Agent Using precursor compound 7 synthesized by the method shown in Example 6, amyloid beta imaging agent 2- [4 ′-(2 ′′-[ 18 F] fluoroethoxy ) Phenyl] -6-iodoimidazo [1,2-a] pyridine ( 18 F-labeled compound 1-9 of International Publication WO2007 / 135890).
  • the amount of radioactivity obtained was 186 MBq (58 minutes after the start of synthesis). Further, when HPLC analysis was performed under the following conditions, it was confirmed that 4 ⁇ g / mL of unreacted precursor compound 7 was mixed. The amount of unreacted precursor compound in the case of using a toluenesulfonic acid ester group instead of the sulfonic acid ester group introduced with the alkylamide tag of the present invention as a leaving group is 650 ⁇ g / mL. According to the invention, it was confirmed that an amyloid beta imaging agent with less contamination of unreacted precursor compound could be synthesized without HPLC purification.
  • Example 8 Synthesis of Precursor Compound 8 According to the following scheme, 2- (2- ⁇ 5-[(1H-imidazol-1-yl) methyl] pyridin-3-yl ⁇ -6-chloro-5-fluoro- 1H-Benzimidazol-1-yl) ethyl-4- (didodecylcarbamoyl) benzenesulfonate (precursor compound 8) was synthesized.
  • Step 1 Synthesis of Precursor Compound 8 2- ⁇ 6-Chloro-5-fluoro-2- [5 obtained by performing Steps 1 to 10 according to the method described in Example 2 of International Publication Pamphlet WO2015 / 199205 -(Imidazol-1-ylmethyl) pyridin-3-yl] benzimidazol-1-yl ⁇ ethanol (57.3 mg, 0.154 mmol) was dissolved in dichloromethane (0.54 mL) and cooled to 0 ° C., then 1 , 8-diazabicyclo [5.4.0] undecene (55.3 ⁇ L, 0.370 mmol), and 4-didodecylcarbamoylbenzenesulfonic acid fluoride obtained by running Step 1 according to the method described in Example 3.
  • Example 9 Synthesis of aldosterone synthase imaging agent Using precursor compound 8 synthesized by the method shown in Example 8, aldosterone synthase imaging agent 6-chloro-5-fluoro-1- (2- [ 18 F] fluoroethyl) -2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] benzimidazole ( 18 F-labeled compound 100 of WO 2015/199205) was prepared.
  • the dimethylsulfoxide solution (0.5 mL) which melt
  • the amount of unreacted precursor compound in the case of using a toluenesulfonic acid ester group instead of the sulfonic acid ester group introduced with the alkylamide tag of the present invention as a leaving group is 115 ⁇ g / mL. According to the invention, it was confirmed that an aldosterone synthase imaging agent with little contamination with unreacted precursor compounds could be synthesized without HPLC purification.

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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un composé précurseur marqué, représenté par la formule (2). (Dans la formule, S représente un substrat, L représente un groupe alkyle linéaire en C1-6 qui peut contenir un groupe éther, R1 et R2 représentent chacun indépendamment un groupe alkyle linéaire ou ramifié en C1-30, ou un groupe aryle monocyclique ou polycyclique fusionné, substitué ou non substitué, chaque R3 représentant indépendamment un groupe alkyle en C1-4 ou un groupe alcoxy en C1-4, et p représente un nombre entier compris entre 0 et 4.)
PCT/JP2018/008287 2017-03-07 2018-03-05 Composé précurseur marqué au fluor radioactif, et procédé de production d'un composé marqué au fluor radioactif utilisant ce dernier WO2018164043A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
AU2018232211A AU2018232211A1 (en) 2017-03-07 2018-03-05 Radioactive fluorine-labeling precursor compound and method for producing radioactive fluorine-labeled compound using same
CN201880012981.8A CN110312704A (zh) 2017-03-07 2018-03-05 放射性氟标记前体化合物及使用其的放射性氟标记化合物的制造方法
CA3055417A CA3055417A1 (fr) 2017-03-07 2018-03-05 Compose precurseur marque au fluor radioactif, et procede de production d'un compose marque au fluor radioactif utilisant ce dernier
ES18764052T ES2909126T3 (es) 2017-03-07 2018-03-05 Compuesto precursor marcador con flúor radiactivo y método para producir un compuesto marcado con flúor radioactivo utilizando el mismo
SG11201908066XA SG11201908066XA (en) 2017-03-07 2018-03-05 Radioactive fluorine-labeled precursor compound, and method for producing radioactive fluorine-labeled compound using same
KR1020197029004A KR20190126357A (ko) 2017-03-07 2018-03-05 방사성 불소 표지 전구체 화합물 및 그것을 사용한 방사성 불소 표지 화합물의 제조 방법
JP2019504564A JP7165853B2 (ja) 2017-03-07 2018-03-05 放射性フッ素標識前駆体化合物及びそれを用いた放射性フッ素標識化合物の製造方法
EP18764052.9A EP3594200B1 (fr) 2017-03-07 2018-03-05 Composé précurseur marqué au fluor radioactif, et procédé de production d'un composé marqué au fluor radioactif utilisant ce dernier
US16/491,046 US20200009273A1 (en) 2017-03-07 2018-03-05 Radioactive fluorine-labeled precursor compound, and method for producing radioactive fluorine-labeled compound using same

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JP2017-042783 2017-03-07
JP2017042783 2017-03-07

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CN (1) CN110312704A (fr)
AU (1) AU2018232211A1 (fr)
CA (1) CA3055417A1 (fr)
ES (1) ES2909126T3 (fr)
SG (1) SG11201908066XA (fr)
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WO2022158442A1 (fr) 2021-01-19 2022-07-28 国立大学法人東京工業大学 Composé précurseur marqué à l'halogène radioactif

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CA3055417A1 (fr) 2018-09-13
AU2018232211A1 (en) 2019-09-26
KR20190126357A (ko) 2019-11-11
EP3594200A1 (fr) 2020-01-15
JPWO2018164043A1 (ja) 2020-01-09
CN110312704A (zh) 2019-10-08
SG11201908066XA (en) 2019-09-27
EP3594200B1 (fr) 2022-03-02
JP7165853B2 (ja) 2022-11-07
EP3594200A4 (fr) 2020-03-11
ES2909126T3 (es) 2022-05-05

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